Alzheimer's disease is a neurodegenerative disease, which is characterized by the degeneration and loss of neuronal cells accompanied by the formation of senile plaques and neurofibrillary tangles. Senile plaque that is the most characteristic in Alzheimer's disease consist of essentially amyloid-β protein (hereinafter referred to as Aβ [see Biochem. Biophys. Res. Commun., 122, 1311 (1984)] and other intracerebral components. It is known that Aβ comprised of 40 or 42 amino acids (hereinafter referred to as Aβ1-40 and Aβ1-42, respectively) is toxic to neurons and induces neurofibrillary changes.
Some patients with familial Alzheimer's disease are known to have APP (amyloid precursor protein) gene mutation, and it is well known that the cells transfected with such mutated gene produce and secrete an increased amount of Aβ [for example, see Nature, 360, 672 (1992); Science, 259, 514 (1993); Science, 264, 1336 (1994), etc.].
Based on the information, medicines which inhibit production and/or secretion are useful for preventing and/or treating diseases caused by Aβ (e.g., Alzheimer's disease, Down's syndrome, etc).
Alternatively, secreted form of amyloid precursor protein (sAPP) is reported to have neurotrophic factor like property (Neuron, 10, 243-254, 1993). As neurotrophic factor like property, 1) survival and preserving effect to the neuronal cell; 2) stimulating the synapse formation; 3) protection of neuronal cell death; and 4) long term potentiation in hippocampus are given as examples. By the above-mentioned property, drugs which stimulate the sAPP secretion are also useful in preventing and treating 1) neurodegenerative diseases such as dementia (e.g., senile dementia, amnesia, etc.), Alzheimer's disease, Down's syndrome, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic sclerosis on lateral fasciculus, Huntington's disease, multiple sclerosis, etc., 2) neurological disorders involved in cerebrovascular disorders (e.g., cerebral infarction, encephalorrhagia, etc.), a head injury or an injury of spinal cord, and so forth.
EP-A-652009 discloses peptide derivatives which is a protease inhibitor exhibiting an Aβ production inhibiting effect in in vitro experiments using cell lines.
On the other hand, the following bicyclic amine compounds are known. 1) JP-A-2-96552 (U.S. Pat. No. 5,137,901) discloses a compound of the formula:
wherein Y represents a straight-chain or branched, substituted or unsubstituted alkylene chain having up to 6 carbon atoms; Z represents a group of the formula: —NR2R3, —OR4, or the like; R2 and R3 are identical or different and represent hydrogen, alkyl, alkenyl or cycloalkyl, or represent aryl which may be substituted by halogen, etc.; R4 represents hydrogen, alkyl, alkenyl, or the like; R1 represents hydrogen, alkyl, aralkyl, heteroarylalkyl or a group of the formula: —(Y1-Z1) in which Y1 and Z1 are identical or different and have the same meanings as Y and Z; A and D each represents a group of the formula: —CH2, O, S or NR13, or the moiety of —CH or N of a double bond C═C or C═NH, with the proviso that either only A or only D represents oxygen, sulfur or N—R13; R13 represents hydrogen, alkyl, alkoxy, acyl, alkoxycarbonyl or alkylsulfonyl; B represents a group of the formula: —CH2 or
or the moiety of —CH or N of a double bond C═C or C═N; C represents a group of the formula:
or the moiety of C of a double bond C═C or C═N; E and F are identical or different and each represents hydrogen, alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy or a group of the formula: —CONR2R3 in which R2 and R3 have the same meanings as above, or E and F together form a substituted or unsubstituted carbocycle having 6 carbon atoms, which is agonist, partial agonist and antagonist on the serotonin receptors and is suitable for the treatment of central nervous system disorders, etc.
2) JP-A-63-77842 discloses a compound of the formula:
wherein n represents 1 or 2; A represents a carbonyl while R7 is hydrogen, or A represents a group of the formula: —CHR8— wherein R8 represents hydrogen, alkanoyloxy or alkoxycarbonyl, while R7 is hydrogen or R7 and R8 together form another bond; E represents a straight-chain alkylene which has 3 or 4 carbon atoms and may be substituted by an alkyl; G represents a straight-chain alkylene which has 2 to 5 carbon atoms and may be substituted by an alkyl; R1 represents hydrogen, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy; R2 represents hydrogen, halogen atoms, hydroxy, alkoxy, phenylalkoxy or alkyl; or R1 and R2 together form an alkylenedioxy having 1 or 2 carbon atoms; R3 represents hydrogen, alkenyl or alkyl having 3 to 5 carbon atoms; R4 represents hydrogen, halogen atoms, alkyl, or the like; R5 represents hydrogen, halogen atoms, alkyl, or the like; and R6 represents hydrogen, halogen atoms, alkyl, or the like, which is suitable for the treatment of sinus tachycardia and also for the prevention and treatment of ischemic heart disease because of its pharmacological action, decrease in the heart rate and oxygen demand of the heart.
3) WO 92/15558 discloses a compound of the formula:
wherein n represents an integer of 1 to 4, which is an intermediate of a compound having a thromboxane A2 antagonistic effect.
4) WO 95/32967 discloses amide derivatives of the formula:
wherein A is CONR where R is hydrogen or C1-6 alkyl; Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R1 is hydrogen, halogen, etc.; R2 and R3 are independently hydrogen, halogen, etc.; R4 and R5 are independently hydrogen or C1-6 alkyl; R6 is halogen, hydroxy, etc.; R7 and R8 are independently hydrogen, C1-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached from an optionally substituted 5 to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur; m is 0 to 4; and n is 0, 1 or 2, which has 5HT1D receptor antagonist activity and is useful for the treatment of various CNS disorders.
5) EP-A-754455 discloses a pharmaceutical compositions for the therapeutic application as neuroprotectors in Parkinson's and Alzheimer's diseases containing a compound of the formula:
wherein X is H, halogen, alkoxy, alkyl, alkylthio, aryl, aryloxy; R is H, CH3 or other aliphatic, alicyclic or aryl radicals; R′ is H, CH3 or other aliphatic or alicyclic C1-C3 radicals, or an aryl or arylalkyl, or a radical the same as those indicated for R″; and R″ is H, CH3 or other aliphatic or alicyclic C1-C3 radicals, or an aryl or arylalkyl, or an acetylene or allene group, being potent selective monoamine oxydase B inhibitors.
The conventional Aβ production inhibitors for the treatment of Alzheimer's disease are problematic in their oral absorbability, stability, etc. and are therefore unsatisfactory as medicines. It is desired to develop a compound which is different from the known compounds mentioned above in its chemical structure and which have an excellent inhibitory effect on Aβ production and/or secretion and is therefore satisfactorily used in medicines.